JPH0358742B2 - - Google Patents

Abstract

A closure for use with a container with pharmaceutically pure contents therein. The elastomeric closure has an elastomeric base and a continuous polyparaxylylene coating on the base. The coating ranges from about 0.5 microns to about 2.0 microns in thickness. The closure member has a coefficient of friction of less than 1.0 and is capable of substantially preventing metal extraction from said elastomers.

Description

[Detailed description of the invention]

FIELD OF INDUSTRIAL APPLICATION The present invention relates to a pharmaceutical product consisting of a container having a pharmaceutically pure content within the container and a resilient lid closing the container. The resilient lid consists of a resilient substrate and a continuous poly(p-
xylylene) coating. BACKGROUND OF THE INVENTION For many years, the most successful closure system for pharmaceutical products has been the use of resilient stoppers on glass or plastic vials. The combination of glass and rubber has been useful as a wide variety of pharmaceutical components that combine both safe storage of drugs and easy access through rubber stoppers.
In particular, when liquid is in the vial, the needle can easily pierce the rubber stopper and extract the desired amount of component without compromising the integrity of the closure. Even when the powder is stored in such a container, the resilient lid is pierced by a syringe needle in order to render the powder usable by adding a liquid such as pure water. Once available, drugs are kept in a safe and protected environment. The success of these types of pharmaceutical devices has led to an increasing number of systems using rubber stoppers for glass containers, and the speed with which these devices can be manufactured is due to the economics of suitable component designs other than the speed. This greatly contributes to efficiency. For example, conventional pharmaceutical equipment used to fill vials relies on mechanically inserting a stopper into the neck of a vial or other shaped container. Immediately before mechanical insertion, the rubber stopper is transferred from the hopper to the closure device, typically by centrifugal force.
Moves by vibration or gravity. It is essential that the rubber components do not stick to each other or get stuck on the moving device. It is essential that they move smoothly into the closure or closure device. The device, particularly the component transfer device, is generally made of stainless steel or other materials that can be kept very clean for pharmaceutical purposes. The ability of a rubber component to glide smoothly over a surface is directly dependent on its coefficient of friction, and a low coefficient of friction is highly preferred. Furthermore, it is important that the resilient components do not stick to each other while moving through the transfer device. In the prior art, the high coefficient of friction of the rubber stoppers and other rubber materials delivered to closure devices and pharmaceutical devices was a limiting factor in device speed.
Whether using gravity or centrifugal or vibratory delivery devices, the rubber stopper or other resilient component is required to move smoothly over the delivery surface as quickly as possible. Typically, rubber devices of the type used for pharmaceutical closures have a diameter of at least 1.2
It has a coefficient of friction of This is clearly an impediment to fast movement and therefore efficient and low-cost production. One solution that has been proposed to improve the general process progression of rubber stoppers, and at least to prevent each rubber stopper from adhering to each other during autoclaving and other processing steps, is to use a coating on the outside of the stopper. is to use silicone oil.
Silicone oil improves the smoothness of the rubber lid, but
At the same time, it presents new problems. The use of silicone oil increases the number of impurity particles found in assays of various drug solutions. The Food and Drug Administration evaluates the process by counting the number of particles present, regardless of their nature or source. Although small amounts of silicone oil are not usually an undesirable contaminant in pharmaceuticals, their use does lead to increased particle counts, thus reducing the overall acceptability of their use in manufacturing equipment. When the amount of silicone oil is minimal, that is, simply the amount needed to prevent each stopper from sticking to each other, the silicone oil provides a uniform and fast transfer for use in high speed capping equipment, especially centrifugal delivery systems. It is not possible to sufficiently lower the friction coefficient of the rubber stopper to the extent that can be obtained. As a result, rubber stoppers that have been treated with the use of silicone oil are never effective in passing chemical tests for compatibility and contamination with the raw materials contained in the vial. Resilient materials used in the pharmaceutical industry are carefully selected and treated to be as inert as possible when in contact with pharmaceutical products such as drugs and their analogs. Formulations and products are constantly tested for contamination. In addition to the number of particles produced by the silicone oil mentioned above, of particular importance are the particles originating from the resilient lid itself. Additionally, certain trace metals are often used in the production of elastic compounds. It is essential that these ingredients are not extracted to an influential concentration by drugs or other pharmaceutical fluids that come into contact with the resilient product. Of particular concern are calcium, aluminum and heavy metals such as zinc and lead. Accelerated and very harsh testing conditions are used to determine the amount of undesirable materials that may leach from resilient materials.
The amount of leached metals produced when the product is subjected to rigorous testing exceeds the concentrations produced under normal conditions that do not result in such contamination of the drug. Currently, containers containing pharmaceutically pure ingredients,
and a resilient substrate sealing the container and a coating on the resilient substrate that substantially improves the coefficient of friction and significantly reduces the amount of leached metal ions that may leach from the resilient lid. No pharmaceutical products have been produced that use elastic caps made of. Various raw materials have been proposed as coating materials for various other general purposes. However, covering the entire surface of resilient closures such as rubber stoppers for use with containers containing pharmaceutically pure ingredients is important in the pharmaceutical industry where the above goals must be met. It was not an acceptable practice. One material that has been found to be very useful as a general coating material is the various paraxylylene polymers. Gorham
US Pat. No. 3,288,728 discloses a basic method for preparing linear copolymers from paraxylylene using temperature conditions of 450°C to 700°C. The patent indicates that small particles can be protected or encapsulated with these polymers that provide the insulating and protective properties of polyxylylene. The reference generally indicates that possible applications for polymers as coating materials can be enumerated. Gorham, US Pat. No. 3,342,754, describes a wide range of methods for preparing linear polymers of paraxylylene and, in particular, coatings using the raw materials.
This patent includes examples of various variations and indicates that these polymers are suitable for use as films, fibers, surface coatings or electrical insulation. Both this patent and the aforementioned Gorham patent provide a general suggestion that almost any material can be coated with paraxylylene polymers, although no specific examples relevant to the pharmaceutical industry are provided. Tittman et al. U.S. Patent No.
No. 3379803 describes special equipment and methods useful for the polymerization of paraxylylene. General disclosures using this raw material indicate that thin, but continuous films can be prepared on a variety of substrates. Related U.S. patent no.
No. 3,472,795 discloses an auxiliary method for increasing the thickness of the coating. Parent, US Pat. No. 4,225,647, discloses a method for coating a wide variety of materials with paraxylylene polymers. The described coating is less than 50 angstroms
The thickness range is 5 mil or more. That patent indicates that a first layer of substituted silicone compound is used before the polyparaxylylene coating. Finally, US Pat. No. 3,300,332 to Gorham et al.
A coating method for coating an object with an insoluble coating is disclosed. Although the thickness of the coating is not detailed, Gorham indicates that the thickness of the coating is not critical and is determined by the final use of the product. He notes that a 0.1 mil coating is very thin and useful when resistance to solvent or reactive attack is desired. As an example, six pieces of rubber are coated to protect against swelling by solvents such as heptane. 0.22g or so
A coating in the range of 0.28g (at least 1 mil thick) was added. Of course, there is no mention of obtaining a coefficient of friction or resistance to metal leaching by various means to provide a superior product for use with drugs. SUMMARY OF THE INVENTION It has thus been discovered to prepare improved pharmaceutical products for use in the following embodiments. The product consists of a container containing a pharmaceutically pure ingredient and a resilient closure that seals the container.
The resilient closure member has a resilient substrate and a continuous polyparaxylylene coating having a thickness of about 0.1 to about 2.0 μm overlying the resilient substrate.
The coating can reduce the coefficient of friction of the lid member to less than 1.0, preferably less than 0.5. The coating can also substantially prevent metal ion leaching from the elastomer. In particular, the coating functions to prevent leaching of metal ions such that leaching of metal ions is 50 to 1000 times less after 1 hour of autoclaving in 1 molar hydrochloric acid. Furthermore,
Substantial reduction or elimination of organic leachables is achieved by practicing the present invention. It has been found that a narrow range of about 0.1 μm to about 2.0 μm is suitable for preparing resilient closure coatings. When the thickness of the covering is 2.0 μm or more, the lid member of the present invention loses elasticity and flexibility, resulting in reduced handling when capping.
There is a risk that the contents will leak out after capping. Furthermore, the force required to puncture the syringe with a needle becomes excessive compared to an uncoated product. The present coating substantially improves the economics of pharmaceutical product production since there is sufficient improvement in the coefficient of friction to allow faster production of the final product. At the same time, the amount of coating used is considerably less than the amount of coating expected to be needed to obtain the protective properties required for this process, which reduces the product price of the polyparaxylylene used. This has sufficiently reduced the proportion of The devices of the present invention can be manufactured from any conventional base material used in pharmaceutical devices where resilient components are required. Such materials are formed into rubber stoppers, plunger tips, prefilled syringes, washers, and other resilient closure members that come into contact with the contents of containers containing pharmaceutically pure materials. The combination of the polyparaxylylene coating and the resilient lid member provides a friction-resistant material that allows for the use of high-speed capping and filling equipment (particularly the use of centrifugal dispensing equipment) with uniform and high-speed movement of the material. Factor less than 1.0, preferably around 0.5
It must be sufficient to reduce the
This coating makes it possible to avoid the use of silicone oil during the process, thereby reducing the particles that appear in the solution that ultimately comes into contact with the resilient closure member. The resilient components of the pharmaceutical devices described herein can be made from most of the resilient compounds conventionally used in the pharmaceutical industry. For example, natural rubber has been used originally as many elastic materials and material components in the pharmaceutical industry. Butyl rubber and many synthetic elastomers have been successfully used as stoppers, plunger tips, and the like due to demands for stability during autoclaving and sterilization. A particularly suitable rubber for the purposes of this invention is butyl rubber. The present invention will be used with all currently existing closures and other elastics available in the pharmaceutical industry. Therefore, any resilient substrate that has been or could be used can be used as the first component of the invention if its coefficient of friction and barrier to metal leaching are suitable. It is expected to be. Currently available Gomuer products are ideal for their purpose in the pharmaceutical industry, except for causing delays in high speed equipment and the possibility of leaching of metal ions. The present invention therefore seeks to improve the functionality of the stopper in these deficiencies while maintaining functionality in the remaining areas. In particular, the present invention is intended to improve the coefficient of friction of the lid member for use in high speed capping equipment, particularly centrifugal delivery equipment. Additionally, the present invention contemplates the removal of silicone oils and other process aids. Ultimately, the present invention contemplates a substantial improvement in preventing metal ion leaching from rubber products that are otherwise well suited for use in the pharmaceutical industry. Additionally, some elastomers contain organic leachables. When applying this second component,
The effectiveness of the rubber raw material as a barrier, as a plug and as a product resistant to chemical attack needs to be maintained. This is because the elastic lids currently in use are optimal except for the drawbacks mentioned above, and there is no meaningful reason to improve their other properties. It is therefore necessary to maintain these properties when applying the coating as described below. Polymers made from various paraxylylenes may be applied as coatings in the manner described in the various patents mentioned above. especially,
As an example of various paraxylylene polymers and copolymers, Gorham U.S. Pat. There is. US Pat. Nos. 3,379,803 and 3,472,795 to Chitman et al. describe methods for applying these particular polymers and copolymers onto a variety of raw materials. These methods have been found to be generally suitable for applying paraxylylene polymers and copolymers to the resilient substrate materials contemplated by this invention. The term polyparaxylylene includes the various paraxylylene polymers and copolymers described in the prior art. As stated above, the coating applied to the resilient substrate of the present invention produces a product with an excellent coefficient of friction. For purposes of the present invention, the coefficient of friction is defined as follows: The coefficient of friction is the ratio of the frictional force resisting movement of the surface being tested to the force normal to that surface. In this case the surface used is a stainless steel plate. Rubber stopper is 256g
weights and placed them on a stainless steel surface. They then increased the slope of the surface until the weight began to slide, fixed the surface at that point, and recorded the angle. The tangent of that angle was taken as the coefficient of static friction. Paraxylylene polymer coatings on resilient substrates improve the coefficient of friction from greater than 1.5 to less than 1.0, and sometimes less than 0.5. Examples In order to demonstrate the effects of the present invention, the following experiments were conducted. In each case, customary rubber stoppers with various applications in the pharmaceutical industry were used. The elastomer used was butyl rubber, commonly known under the trademark 4416/50grayS-127 drug stopper. The rubber stopper was filled with polychloroparaxylylene in the manner described above.
It was coated with a thickness ranging from 0.5 μm or less to 2.0 μm or more. The results in each case represent the average value of many plugs. Table 1 below shows the results of the friction coefficients of various test specimens measured by the method described above.

Table: Another series of experiments was conducted to compare uncoated rubber stoppers of the type described above with those coated with a 1.0 μm thick polyparaxylylene. The tests conducted were conducted in accordance with the United States Pharmacopoeia Test Standards (US
Pharmacopic-National Formulary Testing)
The results are shown in Table 2 below.

Table 2 As can be seen from the comparison in Table 2, the resilient lid member combined with the polyparaxylylene coating generally outperforms the uncoated rubber product. All values for uncoated materials are acceptable by pharmaceutical standards, but the improvements show that the invention does not change the acceptability of the product for the worse, but rather makes it better. ing. To determine the leaching potential of metals, 4416 gray rubber stoppers were autoclaved with 100 ml of 1 molar hydrochloric acid at 120° C. for 1 hour. The acid was analyzed by atomic absorption spectrometry to determine the concentration of zinc and aluminum. Table 3 below shows uncoated rubber stoppers and
The results are shown for a rubber stopper coated with 2 μm polychloroparaxylylene. The degree of improvement is 35 times
It's nearly 1000 times more.

Table: Other tests were conducted to determine the effect of coating thickness on different rubbers and 817 Gray leached metals. The results are shown in Table 4 below. In this series of tests, the stoppers were autoclaved in 1 molar hydrochloric acid for 1 hour, and the acid was analyzed by atomic absorption for various metals. Once again, it has been shown that the invention provides surprising results.

Table: Although the prior art has shown that coating thicknesses of 0.1 μm or less are generally sufficient, within the narrow range of the present invention improvements of 50 to 1000 times are observed. The surprising effects dramatically demonstrate the superiority of the coated elastomers of the present invention in pharmaceutically demanding environments. The effectiveness of polyparaxylylene coatings on various rubber stoppers was also measured to investigate other properties required of pharmaceutical products. Briefly, a series of corings were performed by puncturing each stopper 10 times with a #20 gauge reusable needle. The injection needle was replaced with a new one after every 40 punctures. The contents of the vial were examined through a black filter, but no coating fragments were found. Place uncoated and coated stoppers in steam and water for 1 hour at 121°C.
autoclaved. The uncoated stoppers became sticky and stuck to each other. The coated stopper moved freely and was not sticky, and no damage to the coating was observed. Needle penetrability tests were conducted on uncoated and stoppers coated with 2.0 μm and 25 μm of polyparaxylylene. The test was conducted using a No. 21 gauge disposable double-ended needle with a penetration speed of 5.
It was performed as inch (12.7cm)/minute. The force required to penetrate the uncoated stopper was 312 grams.
324 for a plug coated with 2.0 μm of polyparaxylylene
It was a gram. In this way, the force required to penetrate both was almost the same. In contrast, the force required to penetrate the stopper coated with 25 μm of polyparaxylylene was 568 grams, an increase of 82% compared to the uncoated stopper. Tests have also shown that the amount of organic matter leached is reduced (if not completely prevented). Tests used to determine the amount of particles showed that the polyparaxylylene coating of the closure also improved the flowability of the product during the capping process in a centrifugal delivery device compared to a silicone-treated closure. It clearly shows improved results in providing an increase. Uncoated, coated or siliconized stoppers were placed in 150 ml of filtered deionized water. these
Stir for 30 minutes and count particles in 10 ml of sample. Both the uncoated and coated stoppers had less than 300 particles per total, while the silicone-treated ones had over 10,000 particles per stopper. Finally, various coatings were applied to the rubber stoppers for evaluation in the manufacture of pharmaceutical closures. In particular, pharmaceutical products with containers containing pharmaceutically pure ingredients are
It was sealed by a resilient closure member of the type described herein. These lid members included a resilient lid member having a resilient substrate and a continuous polyparaxylylene coating ranging from about 0.1 μm to about 2.0 μm. The stopper was first autoclaved at 135°C for 12 minutes. It was then subjected to a capping device. These closures have sometimes been rendered unusable because the autoclaving step causes the closures to stick together, thereby causing equipment to shut down. The product prepared according to the invention was then subjected to the above-described autoclaving and capping apparatus. The maximum speed of the plugging equipment is greatly increased and smooth production is achieved without silicone oil, demonstrating the great economy achieved by using the present invention. A variety of pharmaceutical products may be used in containers having the closure member of the present invention. In particular, a test was conducted to evaluate the elasticity of the elastic lid member by capping the container containing medical and pharmaceutical ingredients with the elastic lid member. When 10 lid members not coated with polyparaxylylene were capped, the contents of the container did not leak out, and the lid members had sufficient elasticity. Even when 10 lid members coated with 2.0 μm of polyparaxylylene were capped, the contents of the container did not leak out, and the lid members had sufficient elasticity. On the other hand, when capping was done with a lid coated with polyparaxylylene to a thickness of 25 μm, the contents leaked out of 4 out of 10 lid members, and the elasticity of the lid members was poor. Pharmaceutical products containing veterinary drugs, distilled water, drug-containing solvents, syrups, serums and the like are
Packaging with a resilient lid according to the invention is unaffected.

Claims (1)

[Scope of Claims] 1. A resilient lid member for use with a container containing pharmaceutically pure contents, the resilient lid member comprising an elastic base material and a continuous material covering the resilient base material. The elastic lid member has a friction coefficient of 1.0 or less, and the coating prevents metal ions from leaching from the elastic base material, and has a thickness of about 0.1 μm. ~about 2.0μm
The elastic lid member is within the range of . 2. The elastic lid member according to claim 1, wherein the thickness of the coating is about 0.5 μm to about 2.0 μm. 3. The elastic lid member according to claim 2, wherein the friction coefficient is less than 0.5. 4. The resilient lid member of claim 2, wherein said leaching of calcium ions upon autoclaving in 1 molar hydrochloric acid for 1 hour is at least 50 times less than an uncoated lid member. 5. The resilient lid member of claim 2, wherein the leaching of aluminum ions upon autoclaving in 1 molar hydrochloric acid for 1 hour is at least 50 times less than an uncoated lid member. 6. The resilient closure member of claim 2, wherein said leaching of zinc ions upon autoclaving in 1 molar hydrochloric acid for 1 hour is at least 50 times less than an uncoated closure member. 7. The resilient closure member of claim 1, further comprising a container for containing pharmaceutically pure contents.